Purpose:
Emerging evidence indicates that activation of the angiopoietin (Ang)/Tie2 pathway promotes retinal and choroidal vascular stabilization; however development of a therapeutic approach to Tie2 activation for retinal/choroidal disease has been elusive. Vascular endothelial-protein tyrosine phosphatase (VE-PTP) is an important negative regulator of Tie2 activation. In this study the bioactivity of AKB-9778, a potent and selective small molecule inhibitor of VE-PTP, was assessed.

Methods:
Tie2 phosphorylation was measured by immunoprecipitation in vitro and immunohistochemistry or immunoblots in vivo. The effect of intraocular or systemic AKB-9778 was tested in several models of ocular NV or leakage.

Results:
VE-PTP was upregulated in hypoxic vascular endothelial cells in vitro and in vivo, and was strongly expressed in association with retinal NV. In cultured endothelial cells, AKB-9778 promoted phosphorylation of Tie2, enhanced angiopoietin (Ang)-1-induced Tie2 phosphorylation, and stimulated phosphorylation of signaling molecules in the Tie2 pathway including Akt, eNOS and ERK. AKB-9778 also induced phosphorylation of Tie2 in vivo and strongly suppressed subretinal or retinal NV. Increased expression of Ang-2 stimulated retinal NV, but strongly suppressed it when combined with AKB-9778. In addition to suppressing NV, AKB-9778 blocked VEGF-induced leakage from dermal and retinal vessels and prevented severe leakage and exudative retinal detachment mediated by high expression of VEGF.

Conclusions:
Inhibition of VE-PTP is a novel strategy for Tie2 activation to stabilize retinal and choroidal blood vessels and this approach has potential to provide benefits in patients with a wide variety of retinal and choroidal vascular diseases.